New efficient synthesis of 4-aminocarbonyl substituted 4H-3,1-benzoxazines by a Passerini 3CC/Staudinger/aza-Wittig sequence

Article abstract of DOI:10.1016/j.tet.2009.08.022

α-Acyloxy-carboxamide azides 1, obtained from Passerini reaction of easily accessible o-azidobenzaldehyde with isocyanides and carboxylic acids, reacted with triphenylphosphine to give various 4-aminocarbonyl substituted 4H-1,3-benzoxazines 3 in moderate

Full text of DOI:10.1016/j.tet.2009.08.022

Tetrahedron 65 (2009) 8563–8570
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New efficient synthesis of 4-aminocarbonyl substituted 4H-3,1-benzoxazines
by a Passerini 3CC/Staudinger/aza-Wittig sequence
*
Ping He, Jing Wu, Yi-Bo Nie, Ming-Wu Ding
Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Central China Normal University, Wuhan, 430079, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 April 2009
Received in revised form 14 May 2009
Accepted 3 August 2009
Available online 13 August 2009
a
-Acyloxy-carboxamide azides 1, obtained from Passerini reaction of easily accessible o-azidobenzalde-
hyde with isocyanides and carboxylic acids, reacted with triphenylphosphine to give various 4-amino-
carbonyl substituted 4H-1,3-benzoxazines 3 in moderate to high yields via sequential Staudinger and
intramolecular aza-Wittig reaction. However, a-hydroxy carboxamide azides 5 were obtained in moderate
yields when pyruvic acid was used in the Passerini reaction. Further sequential reaction of azides 5 with
triphenylphosphine and isocyanates produced 2-amino-4-aminocarbonyl substituted 4H-1,3-benzox-
azines 8 via a tandem Staudinger/aza-Wittig/heterocumulene-mediated annulation.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
have been used as fungicidal, herbicidal, anti-inflammatory agents,
C1r serine protease inhibitors, anticonvulsant, and as DNA-binding
The isocyanide based multicomponent reactions (I-MCRs) are
extremely useful tools for synthesis of combinatorial libraries of
compounds and structurally complex molecules.1 Passerini reaction
is one of the main two I-MCRs (Ugi reaction and Passerini reaction)
and is a powerful, atom-economical reaction between isonitrile,
aldehyde (or ketone), and carboxylic acid components that gener-
antitumor agents.6 For example, Etifoxine (A), a nonbenzodiazepine
anticonvulsant drug, has been used for the treatment of psychiatric
illnesses with great therapeutic efficacy and less toxicity.7 There are
many known methods for the synthesis of 4H-3,1-benzoxazines,8
however, 4-aminocarbonyl substituted 4H-3,1-benzoxazines have
not yet been prepared previously probably due to the fact that they
are not easily accessible by routine synthetic method. 4-Amino-
carbonyl substituted 4H-3,1-benzoxazine is a very attractive target
for biochemical studies and drug discovery, due to its large number
of possible substitution patterns and interesting combination of
potential hydrogen bond donors and acceptors on the amide moi-
ety. Recently we have been interested in the synthesis of fused
pyrimidinones and imidazolinones via aza-Wittig reaction, with the
aim of evaluating their biological activities.9 Herein we wish to
report a fundamentally new approach to the synthesis of 4-ami-
nocarbonyl substituted 4H-3,1-benzoxazines by the Passerini re-
action between easily accessible 2-azidobenzaldehyde, isocyanides,
and various acids, followed bya Staudinger/aza-Wittig cyclization of
the Passerini products in the presence of triphenylphosphine
(Fig. 1).
ates a significantly more complex a-acyloxy-carboxamide adduct.
The sequences of classical Passerini isocyanide multicomponent
reactions, followed by post-condensation transformations, consti-
tute extremely powerful synthetic tools for the preparation of
structurally diverse complex molecules, among them are hetero-
cyclic compounds with elaborate substitution patterns.2,3
The aza-Wittig reactions of iminophosphoranes have received
increased attention in view of their utility in the synthesis of ni-
trogen-containing heterocyclic compounds.4 Thus, it is envisioned
that combining the efficiency of the Passerini or Ugi condensation
with a post-condensation aza-Wittig reaction would facilitate ac-
cess to a series of biologically useful heterocycles. The Ugi reaction
with a post aza-Wittig cyclization has been utilized in synthesis of
some dibenzo[b,f]-1,5-diazocine-6(5H)-ones or 1,4-benzodiaze-
pine-5-ones.5 However, to the best of our knowledge, there is no
report about Passerini reaction followed with aza-Wittig reaction to
prepare various substituted heterocycles.
The 4H-3,1-benzoxazine ring system displays important bio-
logical activities and a wide variety of derivatives of this ring system
H3C
Cl
O
N
NHCH2CH3 HCl
A
* Corresponding author. Tel.: þ86 27 63158845; fax: þ86 27 67862041.
E-mail address: ding5229@yahoo.com.cn (M.-W. Ding).
Figure 1. An example of 4H-3,1-benzoxazine drug (Etifoxine).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.022

8564
P. He et al. / Tetrahedron 65 (2009) 8563–8570
Table 2
2. Results and discussion
Preparation of 4-aminocarbonyl substituted 4H-3,1-benzoxazines
molecular aza-Wittig Reaction
3
via intra-
Yield (%)
A
mixture of 2-azidobenzaldehyde10 (1 equiv), isocyanide
Compound
R1
R2
Reaction time (h)
(1 equiv), and various acid (1 equiv) was stirred in methanol at room
temperature for 5–48 h. The Passerini reaction was carried out
smoothly and the products 1 were obtained after recrystallization in
moderate to high yields (58–95%) (Scheme 1 and Table 1). As
indicated in Table 1, high yields were obtained when aliphatic acids
were used (compounds 1a,1b,1f,1k, and 1q). Good yields were also
reached as most of the aromatic acids were utilized whereas mod-
erate yields were obtained when o-substituted aromatic acids were
employed (compounds 1d, 1e, and 1l), which is probably due to the
steric hindrance of the o-substituent.
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
CH3
CH2CH3
3
4
24
36
24
8
24
24
24
24
8
24
24
24
24
24
3
80
83
78
69
89
90
88
79
90
87
86
70
86
80
89
84
92
3,5-2CH3–C6H3
2-CH3–C6H4
2-HO–C6H4
CH2CH2Ph
4-Cl–C6H4
4-NO2–C6H4
4-CH3O–C6H4
Ph
2,4-2Cl–C6H3OCH2
2-Cl–C6H4
4-Cl–C6H4
3-NO2–C6H4
Ph
R1 NC
R1HN
O
O
O
CHO
MeOH
rt
4-CH3O–C6H4
CH2CH3
R2
N3
N3
R2 COOH
1
related to R2 substituent: shorter time (3–8 h) is needed as R2 is
alkyl group (compounds 3a, 3b, 3f, 3k, and 3q) whereas longer time
(24–36 h) is required when R2 is aromatic group.
Scheme 1. Preparation of azides 1 via Passerini reaction.
Table 1
Preparation of azides 1 via Passerini reaction
When pyruvic acid was used in the Passerini reaction as one
of the three reactants,
a-hydroxy carboxamide adduct 5 was
Compound
R1
R2
Reaction time (h)
Yield (%)
isolated as the sole product in moderate yield. The formation of
product 5 can be viewed as an initial Passerini reaction to afford
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
CH3
CH2CH3
5
10
24
48
48
12
24
24
24
24
10
48
24
24
24
24
8
93
89
79
60
62
88
81
78
77
73
83
58
81
80
78
87
95
a
-acyloxy-carboxamide adduct 4, which undergoes further hy-
3,5-2CH3–C6H3
2-CH3–C6H4
2-HO–C6H4
CH2CH2Ph
4-Cl–C6H4
4-NO2–C6H4
4-CH3O–C6H4
Ph
2,4-2Cl–C6H3OCH2
2-Cl–C6H4
4-Cl–C6H4
3-NO2–C6H4
Ph
drolysis during work-up to give 5. The similar hydrolysis reaction
was also encountered as trifluoroacetic acid was utilized in
Table 3
Preparation of compounds 5, 6, 8
Compound
R1
R3
Reaction time (h)
Yield (%)
5a
5b
6a
6b
8a
8b
8c
8d
8e
t-Bu
n-Bu
t-Bu
n-Bu
t-Bu
t-Bu
t-Bu
t-Bu
n-Bu
12
12
4
4
12
6
6
10
6
68
65
87
90
65
60
73
67
71
i-Pr
4-CH3O–C6H4
CH2CH3
4-Cl–C6H4
4-F–C6H4
3-CH3–C6H4
4-Cl–C6H4
The reactions of 1 with triphenylphosphine were examined in
toluene at room temperature for 2 h, followed by heating at reflux
for 3–36 h. Nitrogen evolution via the Staudinger reaction had
ceased during the first 2 h to give iminophosphorane 2, which could
be isolated in good yield, but heating was needed for completion of
the intramolecular aza-Wittig reaction of 2 in a reasonable time to
afford 4-aminocarbonyl substituted 4H-3,1-benzoxazines 3 in 78–
92% yields (Scheme 2 and Table 2). The required heating time is
R1 NC
R1HN
O
O
O
CHO
MeOH
rt
N3
O
N3
O
COOH
4
R1HN
O
R1HN
O
O
R1HN
O
R1HN
O
O
O
O
PPh3
PPh3
R2
OH
R2
OH
PhMe
reflux
N=PPh3
N3
N3
N=PPh3
2
1
5
6
R1HN
O
O
R1HN
O
R1HN
O
R3NCO
-Ph3PO
OH
O
N
R2
N=C=NR3
N
NHR3
3
8
7
Scheme 2. Preparation of 4H-3,1-benzoxazines
3 via intramolecular aza-Wittig
reaction.
Scheme 3. Preparation of 2-amino-4H-3,1-benzoxazines 8.

P. He et al. / Tetrahedron 65 (2009) 8563–8570
8565
Passerini reaction.11 The obtained azide 5 was further reacted
with triphenyl phosphine and the iminophosphorane 6 was
obtained in high yield via Staudinger reaction. When solutions of
iminophosphoranes 6 in dry toluene were treated with iso-
cyanate at reflux temperature, 2-amino-4-aminocarbonyl
substituted 4H-3,1-benzoxazines 8 were isolated as crystalline
solids in moderate yields (Table 3, Scheme 3). Presumably, the
conversion of 6 into 8 involves initial aza-Wittig reaction be-
tween the iminophosphorane 6 and the isocyanate to give a car-
bodiimide 7, which easily undergoes ring closure to give 8.
The structure of 3 and 8 was confirmed by their spectrum data.
Furthermore a single crystal of 3e was obtained from a CH2Cl2 so-
lution of 3e. X-ray structure analysis verified again the proposed
structure (Fig. 2), and showed that the oxazine ring atoms are not
on one plane, but have a torsion angle by 18.91ꢀ, while the dihedral
angle of the two phenyl rings is 19.88ꢀ.
easily prepared from the reaction of sodium azide with 2-nitro-
benzaldehyde according to the literature reports.10
4.2. Synthesis of azides 1 via Passerini reaction
4.2.1. 1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl acetate
(1a). To a solution of 2-azidobenzaldehyde (0.44 g, 3 mmol) in
methanol (15 mL) was added sequentially acetic acid (0.18 g,
3 mmol) and tert-butyl isocyanide (0.25 g, 3 mmol) at room tem-
perature. After the reaction mixture was stirred for 5 h at ambient
temperature, the solvent was removed off under reduced pressure
and the residue was recrystallized from ether/petroleum ether to
give 0.81 g (93%) of azide 1a as white solid. Mp: 82–83 ꢀC, IR (KBr):
3279, 2127, 2095, 1739, 1663, 1557, 1239 cmꢁ1 1H NMR (CDCl3,
.
600 MHz):
d 7.49–7.16 (m, 4H, Ar-H), 6.14 (s, 1H, OCH), 5.96 (s, 1H,
NH), 2.18 (s, 3H, CH3), 1.35 (s, 9H, 3CH3). MS m/z: 248 (MþꢁN3, 21),
131 (100), 93 (47). Anal. Calcd for C14H18N4O3: C, 57.92; H, 6.25; N,
19.30. Found: C, 57.71; H, 6.31; N, 19.42.
4.2.2. 1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl propionate
(1b). Operation as above with propionic acid (0.22 g, 3 mmol) for
10 h, compound 1b (0.81 g, 89%) was also isolated as white solid.
Mp: 96–97 ꢀC, IR (KBr): 3291, 2125, 2098, 1735, 1665, 1558,
1242 cmꢁ1 1H NMR (CDCl3, 600 MHz):
. d 7.47–7.15 (m, 4H, Ar-H),
6.16(s,1H, OCH), 6.00 (s, 1H, NH), 2.51–2.41 (m, 2H, CH2), 1.35 (s, 9H,
3CH3), 1.18 (t, J¼7.2 Hz, 3H, CH3). MS m/z: 262 (MþꢁN3, 12), 150
(73), 134 (100), 92 (36). Anal. Calcd for C15H20N4O3: C, 59.20; H,
6.62; N, 18.41. Found: C, 59.47; H, 6.74; N, 18.35.
4.2.3. 1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl 3,5-dimethyl-
benzoate (1c). Operation as above with 3,5-dimethylbenzoic acid
(0.45 g, 3 mmol) for 24 h, compound 1c (0.90 g, 79%) was also isolated
as white solid. Mp: 161–162 ꢀC, IR (KBr): 3384, 2133, 1698, 1676, 1536,
1254 cmꢁ1. 1H NMR (CDCl3, 600 MHz):
d 7.70–7.17 (m, 7H, Ar-H), 6.41
(s, 1H, OCH), 6.13 (s, 1H, NH), 2.36 (s, 6H, CH3), 1.35 (s, 9H, 3CH3). Anal.
Calcd for C21H24N4O3: C, 66.30; H, 6.36; N, 14.73. Found: C, 66.24; H,
6.13; N, 14.96.
Figure 2. ORTEP diagram of the crystal structure of 3e (Drawn at the 50% thermal
ellipsoids. There are two crystallographic independent molecules in one unit cell. Only
one is shown for clarity).
4.2.4. 1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl 2-methyl-
benzoate (1d). Operation as above with 2-methylbenzoic acid
(0.41 g, 3 mmol) for 48 h, compound 1d (0.66 g, 60%) was also
isolated as white solid. Mp: 91–93 ꢀC, IR (KBr): 3391, 2131, 1708,
3. Conclusion
1687, 1535, 1309, 1217 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
d 8.02–7.16
In conclusion, we are reporting a new MCR, yielding 4-amino-
carbonyl substituted 4H-3,1-benzoxazines, by a sequence of a Pass-
erini reaction, Staudinger reaction, and an intramolecular or tandem
aza-Wittig ring closure. Due to the easy availability of the synthetic
approach and the neutral ring closure condition, this new synthetic
approach discussed here has the potential in synthesis of various
4-aminocarbonyl substituted 4H-3,1-benzoxazines, which are of
considerable interest as potential biological active compounds or
pharmaceuticals.
(m, 8H, Ar-H), 6.39 (s, 1H, OCH), 6.15 (s, 1H, NH), 2.62 (s, 3H, CH3),
1.37 (s, 9H, 3CH3). MS m/z: 267 (MþꢁN2ꢁC4H9, 4),177 (6),118 (100),
91 (17), 57 (10). Anal. Calcd for C20H22N4O3: C, 65.56; H, 6.05; N,
15.29. Found: C, 65.30; H, 6.11; N, 15.14.
4.2.5. 1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl 2-hydroxy-
benzoate (1e). Operation as above with 2-hydroxybenzoic acid
(0.41 g, 3 mmol) for 48 h, compound 1e (0.68 g, 62%) was also
isolated as white solid. Mp: 151–153 ꢀC, IR (KBr): 3313, 2132, 1708,
1646, 1461, 1292, 1122 cmꢁ1. 1H NMR (CDCl3, 600 MHz):
d 10.44 (s,
1H, OH), 7.94–6.91 (m, 8H, Ar-H), 6.40 (s, 1H, OCH), 6.00 (s, 1H, NH),
1.36 (s, 9H, 3CH3). MS m/z: 327 (MþꢁN2, 100), 298 (11), 259 (26),
139 (9). Anal. Calcd for C19H20N4O4: C, 61.95; H, 5.47; N, 15.21.
Found: C, 61.81; H, 5.49; N, 15.29.
4. Experimental
4.1. General
Melting points were uncorrected. MS were measured on a Fin-
nigan Trace MS spectrometer. IR were recorded on a PE-983 infrared
spectrometer as KBr pellets with absorption in cmꢁ1. NMR were
recorded in CDCl3 or DMSO-d6 on a Varian Mercury 400 or 600
spectrometer and resonances relative to TMS. Elementary analyses
were taken on a Vario EL III elementary analysis instrument. The
X-ray diffraction data were collected on a Bruker SMART AXS CCD
4.2.6. 1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl 3-phenyl-
propanoate (1f). Operation as above with 3-phenylpropionic acid
(0.45 g, 3 mmol) for 12 h, compound 1f (1.00 g, 88%) was also iso-
lated as white solid. Mp: 103–104 ꢀC, IR (KBr): 3280, 2129, 2095,
1733, 1662, 1557, 1294, 1177 cmꢁ1 1H NMR (CDCl3, 600 MHz):
.
d
7.43–7.14 (m, 9H, Ar-H), 6.16 (s, 1H, OCH), 5.93 (s, 1H, NH), 3.01–
2.97 (m, 2H, CH2), 2.81–2.75 (m, 2H, CH2), 1.33 (s, 9H, 3CH3). MS m/
z: 281 (MþꢁN2ꢁC4H9, 6), 253 (13), 193 (7), 133 (86), 121 (91), 105
diffractometer, Mo K
a
, 2
q
¼1.86–27.50ꢀ. 2-Azidobenzaldehyde was

8566
P. He et al. / Tetrahedron 65 (2009) 8563–8570
(100). Anal. Calcd for C21H24N4O3: C, 66.30; H, 6.36; N,14.73. Found:
C, 66.48; H, 6.21; N, 14.94.
NCH2), 1.52–1.46 (m, 2H, CH2), 1.34–1.28 (m, 2H, CH2), 0.90 (t,
J¼7.2 Hz, 3H, CH3). Anal. Calcd for C19H19ClN4O3: C, 58.99; H, 4.95;
N, 14.48. Found: C, 59.14; H, 4.75; N, 14.27.
4.2.7. 1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl 4-chloroben-
zoate (1g). Operation as above with 4-chlorobenzoic acid (0.47 g,
3 mmol) for 24 h, compound 1g (0.94 g, 81%) was also isolated as
white solid. Mp: 140–141 ꢀC, IR (KBr): 3288, 2131, 1730, 1655, 1563,
4.2.14. 1-(2-Azidophenyl)-2-(n-butylamino)-2-oxoethyl 3-nitroben-
zoate (1n). Operation as above with 3-nitrobenzoic acid (0.50 g,
3 mmol) for 24 h, compound 1n (0.95 g, 80%) was also isolated as
white solid. Mp: 132–133 ꢀC, IR (KBr): 3286, 2130, 1725, 1661, 1534,
1273, 1094 cmꢁ1. 1H NMR (CDCl3, 600 MHz):
d 8.04–7.20 (m, 8H, Ar-
H), 6.37 (s, 1H, OCH), 6.00 (s, 1H, NH), 1.36 (s, 9H, 3CH3). Anal. Calcd
for C19H19ClN4O3: C, 58.99; H, 4.95; N,14.48. Found: C, 58.93; H, 4.71;
N, 14.62.
1350, 1253 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
d 8.92–7.24 (m, 8H, Ar-
H), 6.49 (s, 1H, OCH), 6.15 (s, 1H, NH), 3.35–3.27 (m, 2H, NCH2),
1.53–1.49 (m, 2H, CH2), 1.34–1.29 (m, 2H, CH2), 0.90 (t, J¼7.2 Hz, 3H,
CH3). MS m/z: 396 (Mþ-1, 4), 369 (4), 242 (25), 150 (100), 104 (34).
Anal. Calcd for C19H19N5O5: C, 57.43; H, 4.82; N, 17.62. Found: C,
57.26; H, 4.95; N, 17.68.
4.2.8. 1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl 4-nitroben-
zoate (1h). Operation as above with 4-nitrobenzoic acid (0.50 g,
3 mmol) for 24 h, compound 1h (0.93 g, 78%) was also isolated as
white solid. Mp: 125–126 ꢀC, IR (KBr): 3284, 2133, 1733, 1664, 1531,
4.2.15. 1-(2-Azidophenyl)-2-(n-butylamino)-2-oxoethyl
benzoate
1275, 1119 cmꢁ1. 1H NMR (CDCl3, 600 MHz):
d
8.32–7.24 (m, 8H, Ar-
(1o). Operation as above with benzoic acid (0.37 g, 3 mmol) for
24 h, compound 1o (0.82 g, 78%) was also isolated as white solꢁid1.
H), 6.38 (s, 1H, OCH), 5.90 (s, 1H, NH), 1.36 (s, 9H, 3CH3). Anal. Calcd
for C19H19N5O5: C, 57.43; H, 4.82; N, 17.62. Found: C, 57.57; H, 4.98;
N, 17.38.
Mp: 113–115 ꢀC, IR (KBr): 3274, 2132, 1716, 1654, 1354, 1248 cm
.
1H NMR (CDCl3, 600 MHz):
d
8.11 (d, J¼7.2 Hz, 2H, Ar-H), 7.62–7.19
(m, 6H, Ar-H), 6.50 (s, 1H, OCH), 6.26 (s, 1H, NH), 3.38–3.25 (m, 2H,
NCH2), 1.53–1.49 (m, 2H, CH2), 1.36–1.30 (m, 2H, CH2), 0.91 (t,
J¼7.2 Hz, 3H, CH3). Anal. Calcd for C19H20N4O3: C, 64.76; H, 5.72; N,
15.90. Found: C, 64.58; H, 5.96; N, 15.84.
4.2.9. 1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl 4-methoxy-
benzoate (1i). Operation as above with 4-methoxybenzoic acid
(0.46 g, 3 mmol) for 24 h, compound 1i (0.88 g, 77%) was also iso-
lated as white solid. Mp: 130–32 ꢀC, IR (KBr): 3283, 2132, 1724,
1662,1606,1259,1169 cmꢁ1. 1H NMR (CDCl3, 600 MHz):
d
8.05–6.94
4.2.16. 1-(2-Azidophenyl)-2-(n-butylamino)-2-oxoethyl 4-methoxy-
benzoate (1p). Operation as above with 4-methoxybenzoic acid
(0.46 g, 3 mmol) for 24 h, compound 1p (1.00 g, 87%) was also
isolated as white solid. Mp: 110–111 ꢀC, IR (KBr): 3277, 2134, 1711,
(m, 8H, Ar-H), 6.39 (s, 1H, OCH), 6.12 (s, 1H, NH), 3.87 (s, 3H, OCH3),
1.37 (s, 9H, 3CH3). Anal. Calcd for C20H22N4O4: C, 62.82; H, 5.80; N,
14.65. Found: C, 62.64; H, 5.94; N, 14.85.
1671, 1258, 1165 cmꢁ1 1H NMR (CDCl3, 600 MHz):
. d 8.05 (d,
4.2.10. 1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl benzoate
(1j). Operation as above with benzoic acid (0.37 g, 3 mmol) for
24 h, compound 1j (0.77 g, 73%) was also isolated as white solid.
Mp: 136–137 ꢀC, IR (KBr): 3303, 2125, 1722, 1670, 1560, 1255,
J¼8.4 Hz, 2H, Ar-H), 7.60–7.19 (m, 4H, Ar-H), 6.94 (d, J¼8.4 Hz, 2H,
Ar-H), 6.47 (s, 1H, OCH), 6.28 (s, 1H, NH), 3.86 (s, 3H, OCH3), 3.36–
3.25 (m, 2H, NCH2), 1.52–1.50 (m, 2H, CH2), 1.35–1.31 (m, 2H, CH2),
0.91 (t, J¼7.2 Hz, 3H, CH3). Anal. Calcd for C20H22N4O4: C, 62.82; H,
5.80; N, 14.65. Found: C, 62.95; H, 5.63; N, 14.68.
1113 cmꢁ1 1H NMR (CDCl3, 600 MHz):
. d 8.11–7.18 (m, 9H, Ar-H),
6.41 (s, 1H, OCH), 6.13 (s, 1H, NH), 1.38 (s, 9H, 3CH3). Anal. Calcd for
C19H20N4O3: C, 64.76; H, 5.72; N, 15.90. Found: C, 64.81; H, 5.63; N,
15.63.
4.2.17. 1-(2-Azidophenyl)-2-(n-butylamino)-2-oxoethyl propionate
(1q). Operation as above with propionic acid (0.22 g, 3 mmol) for
8 h, compound 1q (0.87 g, 95%) was also isolated as white solid.
Mp: 85–86 ꢀC, IR (KBr): 3312, 2107, 1739, 1660, 1543, 1179 cmꢁ1. 1H
4.2.11. 1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl 2-(2,4-di-
chlorophenoxy) acetate (1k). Operation as above with 2-(2,4-
dichlorophenyloxy)acetic acid (0.66 g, 3 mmol) for 10 h, compound
1k (1.12 g, 83%) was also isolated as white solid. Mp: 95–96 ꢀC, IR
NMR (CDCl3, 400 MHz): d 7.50–7.15 (m, 4H, Ar-H), 6.25 (s, 1H, OCH),
6.19 (s, 1H, NH), 3.32–3.22 (m, 2H, NCH2), 2.52–2.43 (m, 2H, CH2),
1.52–1.46 (m, 2H, CH2), 1.34–1.27 (m, 2H, CH2), 1.18 (t, J¼7.6 Hz, 3H,
CH3), 0.91 (t, J¼7.2 Hz, 3H, CH3). Anal. Calcd for C15H20N4O3: C,
59.20; H, 6.62; N, 18.41. Found: C, 59.36; H, 6.43; N, 18.67.
(KBr): 3380, 2136, 1753, 1681, 1482, 1196, 1091 cmꢁ1
.
1H NMR
(CDCl3, 600 MHz):
d 7.40–6.79 (m, 7H, Ar-H), 6.21 (s, 1H, OCH), 5.97
(s, 1H, NH), 4.81 (s, 2H, CH2O), 1.32 (s, 9H, 3CH3). MS m/z: 450 (Mþ,
14), 350 (10), 288 (50), 260 (52), 220 (74), 175 (81), 134 (100). Anal.
Calcd for C20H20Cl2N4O4: C, 53.23; H, 4.47; N,12.41. Found: C, 53.37;
H, 4.59; N, 12.34.
4.3. Synthesis of some iminophosphoranes 2 via Staudinger
reaction
4.3.1. 2-(tert-Butylamino)-1-(2-(triphenylphosphoranylidene) amino-
phenyl)-2-oxoethyl 4-nitrobenzoate (2h). To a stirred solution of
azide 1h (0.40 g, 1 mmol) in toluene (10 mL) was added dropwise
triphenylphosphine (0.26 g, 1 mmol) in toluene (5 mL) at room
temperature. After the reaction mixture was stirred for 2 h at am-
bient temperature, the solvent was removed off under reduced
pressure and the residual was recrystallized from methylene
dichloride/petroleum ether to give 0.58 g (92%) of iminophosphor-
ane 2h as white solid. Mp: 210–213 ꢀC, IR (KBr): 3210, 1725, 1687,
4.2.12. 1-(2-Azidophenyl)-2-(n-butylamino)-2-oxoethyl 2-chloroben-
zoate (1l). Operation as above with 2-chlorobenzoic acid (0.47 g,
3 mmol) for 48 h, compound 1l (0.67 g, 58%) was also isolated as
white solid. Mp: 68–69 ꢀC, IR (KBr): 3289, 2124, 1730, 1656, 1252,
1104 cmꢁ1 1H NMR (CDCl3, 400 MHz):
. d 7.96–7.18 (m, 8H, Ar-H),
6.54 (s, 1H, NH), 6.52 (s, 1H, CHO), 3.40–3.28 (m, 2H, NCH2), 1.57–
1.49 (m, 2H, CH2), 1.40–1.33 (m, 2H, CH2), 0.92 (t, J¼7.2 Hz, 3H, CH3).
Anal. Calcd for C19H19ClN4O3: C, 58.99; H, 4.95; N, 14.48. Found: C,
58.77; H, 4.88; N, 14.71.
1526, 1319, 1261, 1114 cmꢁ1. 1H NMR (CDCl3, 600 MHz):
d 8.56 (s, 1H,
CONH), 8.42–6.54 (m, 24H, Ar-H and OCH),1.07 (s, 9H, 3CH3). MS m/z:
631 (Mþ, 26), 482 (100), 382 (46), 261 (57), 253 (59), 183 (50). Anal.
Calcd for C37H34N3O5P: C, 70.35; H, 5.43; N, 6.65. Found: C, 70.51; H,
5.67; N, 6.38.
4.2.13. 1-(2-Azidophenyl)-2-(n-butylamino)-2-oxoethyl
4-chloro-
benzoate (1m). Operation as above with 4-chlorobenzoic acid
(0.47 g, 3 mmol) for 24 h, compound 1m (0.94 g, 81%) was also
isolated as white solid. Mp: 122–124 ꢀC, IR (KBr): 3299, 2131, 1725,
1665, 1258, 1096 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
d
8.05–7.19 (m,
4.3.2. 2-(tert-Butylamino)-1-(2-(triphenylphosphoranylidene) amino-
8H, Ar-H), 6.46 (s, 1H, OCH), 6.20 (br, 1H, NH), 3.44–3.25 (m, 2H,
phenyl)-2-oxoethyl benzoate (2j). Operation as above with azide

P. He et al. / Tetrahedron 65 (2009) 8563–8570
8567
1j (0.35 g, 1 mmol), compound 2j (0.52 g, 88%) was also isolated as
1103 cmꢁ1
.
1H NMR (CDCl3, 400 MHz):
d
7.84–7.24 (m, 8H, Ar-H),
white solid. Mp: 212–213 ꢀC, IR (KBr): 3203, 1724, 1684, 1591, 1480,
6.18 (s, 1H, CONH), 5.67 (s, 1H, OCH), 2.63 (s, 3H, CH3), 1.35 (s, 9H,
1261, 1112 cmꢁ1
.
1H NMR (CDCl3, 400 MHz):
d
8.51 (s, 1H, CONH),
3CH3). 13C NMR (CDCl3, 100 MHz):
d
166.7, 156.7, 138.3, 131.7, 131.5,
8.25–6.51 (m, 25H, Ar-H and OCH), 1.06 (s, 9H, 3CH3). MS m/z: 586
(Mþ, 19), 481 (100), 380 (63), 353 (31), 277 (46), 209 (81), 183 (94),
105 (99). Anal. Calcd for C37H35N2O3P: C, 75.75; H, 6.01; N, 4.78.
Found: C, 75.54; H, 6.12; N, 4.61.
130.8, 129.6, 129.5, 127.4, 125.9, 125.0, 124.5, 120.6, 75.4, 51.5, 28.5,
21.7. MS m/z: 322 (Mþ, 27), 222 (100), 195 (31), 165 (19), 130 (15),
116 (13). Anal. Calcd for C20H22N2O2: C, 74.51; H, 6.88; N, 8.69.
Found: C, 74.78; H, 6.74; N, 8.75.
4.3.3. 2-(tert-Butylamino)-1-(2-(triphenylphosphoranylidene) amino-
phenyl)-2-oxoethyl 2-(2,4-dichlorophenoxy) acetate (2k). Operation
as above with azide 1k (0.45 g, 1 mmol), compound 2k (0.62 g, 90%)
was also isolated as white solid. Mp: 159–161 ꢀC, IR (KBr): 3189,1764,
4.4.5. N-(tert-Butyl)-2-(2-methylphenyl)-4H-3,1-benzoxazine-4-car-
boxamide (3e). Operation as above with azide 1e (0.37 g, 1 mmol)
refluxed for 24 h, compound 3e (0.29 g, 89%) was also isolated as
white solid. Mp: 151–152 ꢀC, IR (KBr): 3303, 1658, 1601, 1571, 1246,
1678, 1592, 1480, 1325, 1196 cmꢁ1. 1H NMR (CDCl3, 600 MHz):
d
8.46
1091 cmꢁ1. 1H NMR (CDCl3, 600 MHz):
d
13.25 (s, 1H, OH), 7.82 (d,
J¼7.2 Hz,1H, Ar-H), 7.47–6.91 (m, 7H, Ar-H), 6.18 (s, 1H, CONH), 5.69
(s, 1H, OCH), 1.35 (s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
166.3,
(s, 1H, CONH), 7.72–6.50 (m, 23H, Ar-H and OCH), 5.01, 4.91 (dd,
J¼16.2 Hz, 2H, CH2O), 1.03 (s, 9H, 3CH3). MS m/z: 684 (Mþ, 11), 598
(16), 576 (18), 433 (12), 307 (100), 289 (16), 263 (12), 149 (13). Anal.
Calcd for C38H35Cl2N2O4P: C, 66.57; H, 5.15; N, 4.09. Found: C, 66.63;
H, 5.29; N, 4.21.
d
161.2, 157.0, 135.6, 134.1, 129.7, 127.5, 127.0, 125.4, 123.9, 120.3, 118.8,
117.7, 113.0, 75.5, 51.7, 28.5. MS m/z: 324 (Mþ, 96), 224 (100), 196
(99),180 (88),166 (31),105 (9). Anal. Calcd for C19H20N2O3: C, 70.35;
H, 6.21; N, 8.64. Found: C, 70.08; H, 6.15; N, 8.78.
4.4. Synthesis of 4H-3,1-benzoxazines 3 via intramolecular
aza-Wittig reaction
4.4.6. N-(tert-Butyl)-2-phenylethyl-4H-3,1-benzoxazine-4-carbox-
amide (3f). Operation as above with azide 1f (0.38 g, 1 mmol)
refluxed for 8 h, compound 3f (0.30 g, 90%) was also isolated as
white solid. Mp: 99–100 ꢀC, IR (KBr): 3290, 1657, 1602, 1552, 1363,
4.4.1. N-(tert-Butyl)-2-methyl-4H-3,1-benzoxazine-4-carboxamide
(3a). To a stirred solution of azide 1a (0.29 g, 1 mmol) in toluene
(10 mL) was added dropwise triphenylphosphine (0.26 g, 1 mmol)
in toluene (5 mL) at room temperature. After the reaction mixture
was stirred for 2 h at room temperature and then for 3 h at reflux
temperature, the solvent was removed off under reduced pressure
and the residual was recrystallized from methanol to give 0.20 g
(80%) of compound 3a as white solid. Mp: 157–158 ꢀC, IR (KBr):
1163 cmꢁ1 1H NMR (CDCl3, 600 MHz):
. d 7.41–7.16 (m, 9H, Ar-H),
6.03 (s,1H, CONH), 5.46 (s,1H, OCH), 3.08–3.04 (m, 2H, CH2), 2.75 (t,
J¼7.2 Hz, 2H, CH2), 1.35 (s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
d
166.8, 159.6, 140.3, 137.4, 129.4, 128.4, 128.2, 126.9, 126.2, 124.6,
124.4,120.2, 75.1, 51.4, 36.4, 32.0, 28.4. MS m/z: 337 (Mþþ1, 62), 236
(100), 218 (44), 145 (43), 116 (38), 91 (97). Anal. Calcd for
C21H24N2O2: C, 74.97; H, 7.19; N, 8.33. Found: C, 74.89; H, 7.11; N,
8.52.
3290, 1676, 1642, 1541, 1218 cmꢁ1
7.42–7.13 (m, 4H, Ar-H), 6.07 (s, 1H, CONH), 5.50 (s, 1H, OCH), 2.21
(s, 3H, CH3), 1.38 (s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
166.9,
.
1H NMR (CDCl3, 600 MHz):
d
d
157.8, 137.4, 129.5, 127.0, 124.8, 124.2, 120.1, 75.2, 51.5, 28.6, 21.5. MS
m/z: 146 (MþꢁCONHBu, 100), 104 (11), 77 (23), 57 (34). Anal. Calcd
for C14H18N2O2: C, 68.27; H, 7.37; N, 11.37. Found: C, 68.34; H, 7.56;
N, 11.32.
4.4.7. N-(tert-Butyl)-2-(4-chlorophenyl)-4H-3,1-benzoxazine-4-car-
boxamide (3g). Operation as above with azide 1g (0.39 g, 1 mmol)
refluxed for 24 h, compound 3g (0.30 g, 88%) was also isolated as
white solid. Mp: 144–146 ꢀC, IR (KBr): 3299, 1660, 1629, 1551, 1248,
1094 cmꢁ1. 1H NMR (CDCl3, 600 MHz):
d
8.09 (d, J¼7.8 Hz, 2H, Ar-
H), 7.45–7.24 (m, 6H, Ar-H), 6.12 (s, 1H, CONH), 5.66 (s, 1H, OCH),
1.34 (s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
166.8, 153.8, 138.0,
4.4.2. N-(tert-Butyl)-2-ethyl-4H-3,1-benzoxazine-4-carboxamide
(3b). Operation as above with azide 1b (0.30 g, 1 mmol) refluxed
for 4 h, compound 3b (0.22 g, 83%) was also isolated as white solꢁid1.
d
137.8, 130.1, 129.6, 129.0, 128.7, 127.4, 125.1, 124.9, 120.7, 75.6, 51.5,
28.5. MS m/z: 341 (Mþ-1, 37), 238 (98), 213 (100), 177 (58), 138 (82),
111 (50). Anal. Calcd for C19H19ClN2O2: C, 66.57; H, 5.59; N, 8.17.
Found: C, 66.73; H, 5.38; N, 8.34.
Mp: 109–110 ꢀC, IR (KBr): 3353, 1676, 1635, 1532, 1363, 1169 cm
.
1H NMR (CDCl3, 600 MHz):
d 7.41–7.14 (m, 4H, Ar-H), 6.14 (s, 1H,
CONH), 5.50 (s, 1H, OCH), 2.46 (q, J¼7.2 Hz, 2H, CH2). 1.37 (s, 9H,
3CH3), 1.28 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz):
d
167.0, 161.1, 137.3, 129.2, 126.7, 124.8, 124.3, 120.1, 75.0, 51.3, 28.4,
4.4.8. N-(tert-Butyl)-2-(4-nitrophenyl)-4H-3,1-benzoxazine-4-car-
boxamide (3h). Operation as above with azide 1h (0.40 g, 1 mmol)
refluxed for 24 h, compound 3h (0.30 g, 79%) was also isolated as
white solid. Mp: 180–181 ꢀC, IR (KBr): 3307, 1660, 1631, 1597, 1522,
28.1, 10.3. MS m/z: 260 (Mþ, 5), 160 (100), 131 (50), 104 (20), 76 (27).
Anal. Calcd for C15H20N2O2: C, 69.20; H, 7.74; N, 10.76. Found: C,
69.33; H, 7.51; N, 10.74.
1346, 1091 cmꢁ1. 1H NMR (CDCl3, 600 MHz):
d
8.32–7.29 (m, 8H, Ar-
H), 6.01 (s, 1H, CONH), 6.00 (s, 1H, OCH), 1.36 (s, 9H, 3CH3). 13C NMR
(CDCl3, 150 MHz): 166.5, 152.8, 149.5, 137.5, 129.8, 128.6, 128.1,
4.4.3. N-(tert-Butyl)-2-(3,5-dimethylphenyl)-4H-3,1-benzoxazine-4-
carboxamide (3c). Operation as above with azide 1c (0.38 g,
1 mmol) refluxed for 24 h, compound 3c (0.26 g, 78%) was also
isolated as white solid. Mp: 144–146 ꢀC, IR (KBr): 3277, 1650, 1557,
d
125.6, 124.8, 123.5, 120.7, 75.9, 51.7, 28.5. MS m/z: 253
(MþꢁBuNHCO, 22), 207 (14), 105 (28), 91 (24), 77 (56), 57 (100).
Anal. Calcd for C19H19N3O4: C, 64.58; H, 5.42; N, 11.89. Found: C,
64.65; H, 5.31; N, 11.97.
1248, 1083 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
d
7.70–7.17 (m, 7H, Ar-
H), 6.23 (s, 1H, CONH), 5.65 (s, 1H, OCH), 2.39 (s, 6H, 2CH3), 1.33 (s,
9H, 3CH3). 13C NMR (CDCl3, 100 MHz):
167.1, 155.0, 138.1, 138.0,
d
133.6, 131.5, 129.5, 127.0, 125.4, 125.1, 124.9, 120.9, 75.5, 51.5, 28.1,
21.2. MS m/z: 336 (Mþ, 57), 231 (99), 206 (65), 192 (100), 165 (64),
105 (51). Anal. Calcd for C21H24N2O2: C, 74.97; H, 7.19; N, 8.33.
Found: C, 74.92; H, 7.04; N, 8.56.
4.4.9. N-(tert-Butyl)-2-(4-methoxyphenyl)-4H-3,1-benzoxazine-4-
carboxamide (3i). Operation as above with azide 1i (0.38 g,
1 mmol) refluxed for 24 h, compound 3i (0.31 g, 90%) was also
isolated as white solid. Mp: 121–122 ꢀC, IR (KBr): 3322, 3060, 1663,
1623, 1572, 1254, 1098 cmꢁ1. 1H NMR (CDCl3, 600 MHz):
d 8.10 (d,
4.4.4. N-(tert-Butyl)-2-(2-methylphenyl)-4H-3,1-benzoxazine-4-car-
boxamide (3d). Operation as above with azide 1d (0.37 g, 1 mmol)
refluxed for 36 h, compound 3d (0.22 g, 69%) was also isolated as
white solid. Mp: 140–142 ꢀC, IR (KBr): 3336, 1664, 1593, 1535, 1210,
J¼8.4 Hz, 2H, Ar-H), 7.45–7.20 (m, 4H, Ar-H), 6.97 (d, J¼9.0 Hz, 2H,
Ar-H), 6.19 (s, 1H, CONH), 5.63 (s, 1H, OCH), 3.86 (s, 3H, OCH3), 1.33
(s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
d
167.1, 162.6, 154.6, 138.3,
129.5, 129.4, 126.7, 124.9, 124.7, 123.9, 120.8, 113.8, 75.5, 55.3, 51.4,

8568
P. He et al. / Tetrahedron 65 (2009) 8563–8570
28.5. MS m/z: 338 (Mþ, 59), 253 (10), 237 (100), 210 (36), 195 (29),
133 (32). Anal. Calcd for C20H22N2O3: C, 70.99; H, 6.55; N, 8.28.
Found: C, 70.74; H, 6.38; N, 8.46.
Anal. Calcd for C19H19N3O4: C, 64.58; H, 5.42; N, 11.89. Found: C,
64.31; H, 5.57; N, 11.82.
4.4.15. N-(n-Butyl)-2-phenyl-4H-3,1-benzoxazine-4-carboxamide
(3o). Operation as above with azide 1o (0.35 g, 1 mmol) refluxed
for 24 h, compound 3o (0.27 g, 89%) was also isolated as whiteꢁs1olid.
4.4.10. N-(tert-Butyl)-2-phenyl-4H-3,1-benzoxazine-4-carboxamide
(3j). Operation as above with azide 1j (0.35 g, 1 mmol) refluxed for
24 h, compound 3j (0.27 g, 87%) was also isolated as white solꢁid1.
Mp: 131–133 ꢀC, IR (KBr): 3262, 1649, 1574, 1239, 1094 cm
.
1H
Mp: 155–156 ꢀC, IR (KBr): 3305, 1658, 1627, 1549, 1249, 1099 cm
.
NMR (CDCl3, 400 MHz):
d
8.17 (d, J¼8.0 Hz, 2H, Ar-H), 7.55–7.23 (m,
1H NMR (CDCl3, 600 MHz):
Ar-H), 6.19 (s, 1H, CONH), 5.68 (s, 1H, OCH), 1.34 (s, 9H, 3CH3). 13
NMR (CDCl3, 150 MHz): 167.0, 154.7, 138.0, 131.9, 131.7, 129.6,
d
8.16 (d, 2H, Ar-H), 7.55–7.25 (m, 6H,
7H, Ar-H), 6.35 (s, 1H, CONH), 5.82 (s, 1H, OCH), 3.34–3.28 (m, 2H,
NCH2), 1.48–1.42 (m, 2H, CH2), 1.30–1.24 (m, 2H, CH2), 0.85 (t,
C
d
J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz):
d 167.9, 154.6, 137.9,
128.5, 127.7, 127.2, 125.1, 125.0, 120.9, 75.6, 51.5, 28.6. MS m/z: 308
(Mþ, 3), 208 (98), 180 (39), 152 (46), 105 (24), 77 (100). Anal. Calcd
for C19H20N2O2: C, 74.00; H, 6.54; N, 9.08. Found: C, 74.16; H, 6.41;
N, 9.29.
131.9, 131.5, 129.6, 128.6, 127.8, 127.3, 125.2, 125.0, 120.5, 75.5, 39.1,
31.3, 19.9, 13.6. MS m/z: 208 (MþꢁBuNHCO, 73), 179 (15), 152 (24),
104 (27), 77 (100). Anal. Calcd for C19H20N2O2: C, 74.00; H, 6.54; N,
9.08. Found: C, 74.28; H, 6.41; N, 9.15.
4.4.11. N-(tert-Butyl)-2-((2,4-dichlorophenoxy)methyl)-4H-3,1-ben-
zoxazine-4-carboxamide (3k). Operation as above with azide 1k
(0.45 g, 1 mmol) refluxed for 8 h, compound 3k (0.35 g, 86%) was
also isolated as white solid. Mp: 123–124 ꢀC, IR (KBr): 3285, 1653,
4.4.16. N-(n-Butyl)-2-(4-methoxyphenyl)-4H-3,1-benzoxazine-4-
carboxamide (3p). Operation as above with azide 1p (0.38 g,
1 mmol) refluxed for 24 h, compound 3p (0.28 g, 84%) was also
isolated as white solid. Mp: 128–130 ꢀC, IR (KBr): 3272, 1654, 1626,
1484, 1296, 1068 cmꢁ1. 1H NMR (CDCl3, 600 MHz):
d
7.46–7.11 (m,
1574, 1253, 1097 cmꢁ1 1H NMR (CDCl3, 400 MHz):
. d 8.10 (d,
7H, Ar-H), 6.45 (s,1H, CONH), 5.60 (s,1H, OCH), 4.81 (dd, J1¼13.2 Hz,
J¼8.8 Hz, 2H, Ar-H), 7.46–7.19 (m, 4H, Ar-H), 6.97 (d, J¼8.8 Hz, 2H,
Ar-H), 6.38 (s, 1H, CONH), 5.75 (s, 1H, OCH), 3.86 (s, 3H, OCH3),
3.32–3.27 (m, 2H, NCH2), 1.47–1.41 (m, 2H, CH2), 1.29–1.24 (m, 2H,
J2¼10.8 Hz, 2H, CH2), 1.25 (s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
d
166.8, 154.4, 152.7, 136.1, 130.3, 129.6, 128.0, 127.9, 126.2, 124.9,
124.7, 120.7, 116.8, 75.2, 70.2, 51.7, 28.4. MS m/z: 406 (Mþ, 16), 371
(6), 307 (76), 288 (14), 146 (100), 117 (25). Anal. Calcd for
C20H20Cl2N2O3: C, 58.98; H, 4.95; N, 6.88. Found: C, 58.87; H, 4.84;
N, 6.96.
CH2), 0.86 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz):
d 168.0,
162.6, 154.6, 138.2, 129.6, 129.5, 126.7, 124.9, 124.8, 123.9, 120.4,
113.8, 75.4, 55.4, 39.1, 31.3, 19.8, 13.6. MS m/z: 338 (Mþ, 12), 238
(100). Anal. Calcd for C20H22N2O3: C, 70.99; H, 6.55; N, 8.28. Found:
C, 70.91; H, 6.68; N, 8.07.
4.4.12. N-(n-Butyl)-2-(2-chlorophenyl)-4H-3,1-benzoxazine-4-car-
boxamide (3l). Operation as above with azide 1l (0.39 g, 1 mmol)
refluxed for 24 h, compound 3l (0.24 g, 70%) was also isolated as
white solid. Mp: 91–92 ꢀC, IR (KBr): 3254, 1652, 1579, 1436, 1236,
4.4.17. N-(n-Butyl)-2-ethyl-4H-3,1-benzoxazine-4-carboxamide
(3q). Operation as above with azide 1q (0.30 g, 1 mmol) refluxed
for 3 h, compound 3q (0.24 g, 92%) was also isolated as white solid.
Mp: 79–80 ꢀC, IR (KBr): 3347, 1672, 1633, 1530, 1368, 1174 cmꢁ1. 1H
1102 cmꢁ1 1H NMR (CDCl3, 400 MHz):
. d 7.84–7.26 (m, 8H, Ar-H),
6.70 (s, 1H, CONH), 5.88 (s, 1H, OCH), 3.37–3.31 (m, 2H, NCH2), 1.54–
NMR (CDCl3, 400 MHz): d 7.44–7.15 (m, 4H, Ar-H), 6.27 (s, 1H,
1.47 (m, 2H, CH2), 1.37–1.28 (m, 2H, CH2), 0.85 (t, J¼7.2 Hz, 3H, CH3).
CONH), 5.64 (s, 1H, OCH), 3.35–3.29 (m, 2H, NCH2), 2.48 (q,
J¼7.6 Hz, 2H, CH2), 1.54–1.47 (m, 2H, CH2), 1.38–1.27 (m, 5H, CH2
and CH3), 0.92 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz):
13C NMR (CDCl3, 100 MHz):
d 167.3, 155.2, 137.6, 132.6, 131.8, 131.4,
130.5, 129.6, 127.9, 127.0, 125.3, 124.6, 120.1, 75.3, 39.1, 31.3, 19.9,
13.6. MS m/z: 342 (Mþ, 22), 239 (100), 215 (27), 177 (43), 150 (44),
76 (91). Anal. Calcd for C19H19ClN2O2: C, 66.57; H, 5.59; N, 8.17.
Found: C, 66.42; H, 5.48; N, 8.27.
d
167.9, 161.4, 137.3, 129.5, 126.8, 124.8, 124.4, 119.9, 74.9, 39.0, 31.3,
28.2, 19.9, 13.6, 10.4. MS m/z: 261 (Mþþ1, 31), 160 (93), 131 (34), 91
(100), 77 (38). Anal. Calcd for C15H20N2O2: C, 69.20; H, 7.74; N,10.76.
Found: C, 69.14; H, 7.87; N, 10.98.
4.4.13. N-(n-Butyl)-2-(4-chlorophenyl)-4H-3,1-benzoxazine-4-car-
boxamide (3m). Operation as above with azide 1m (0.39 g, 1 mmol)
refluxed for 24 h, compound 3m (0.24 g, 70%) was also isolated as
white solid. Mp: 166–167 ꢀC, IR (KBr): 3299, 1660, 1632, 1489, 1235,
4.5. Synthesis of azides 5 via Passerini reaction
4.5.1. 2-(2-Azidophenyl)-N-(tert-butyl)-2-hydroxyacetamide
(5a). To a solution of 2-azidobenzaldehyde (0.44 g, 3 mmol) in
methanol (15 mL) was added sequentially pyruvic acid (0.26 g,
3 mmol) and tert-butyl isocyanide (0.25 g, 3 mmol) at room tem-
perature. After the reaction mixture was stirred for 12 h at ambient
temperature, the solvent was removed off under reduced pressure
and the residue was chromatographed on silicon gel to give 0.51 g
(68%) of azide 5a as white solid. Mp: 129–131 ꢀC, IR (KBr): 3391,
1100 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
d
8.08 (d, J¼8.8 Hz, 2H, Ar-
H), 7.44–7.20 (m, 6H, Ar-H), 6.42 (s, 1H, CONH), 5.77 (s, 1H, OCH),
3.29 (q, J¼6.8 Hz, 2H, NCH2), 1.48–1.41 (m, 2H, CH2), 1.31–1.23 (m,
2H, CH2), 0.86 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz):
d
167.7, 153.8, 138.0, 137.7, 131.9, 130.0, 129.6, 129.1, 128.7, 128.5,
127.3, 125.1, 124.8, 120.4, 75.5, 39.1, 31.3, 19.8, 13.6. MS m/z: 342
(Mþ, 7), 244 (100), 179 (10), 139 (24), 77 (10). Anal. Calcd for
C19H19ClN2O2: C, 66.57; H, 5.59; N, 8.17. Found: C, 66.48; H, 5.74; N,
8.09.
.
3226, 2135, 2098, 1652, 1526, 1309, 1067 cmꢁ1 1H NMR (CDCl3,
600 MHz): 7.44–7.16 (m, 4H, Ar-H), 6.28 (s, 1H, CONH), 5.18 (s, 1H,
d
OCH), 4.15 (s, 1H, OH), 1.32 (s, 9H, 3CH3). Anal. Calcd for
C12H16N4O2: C, 58.05; H, 6.50; N, 22.57. Found: C, 58.28; H, 6.37; N,
22.71.
4.4.14. N-(n-Butyl)-2-(3-nitrophenyl)-4H-3,1-benzoxazine-4-car-
boxamide (3n). Operation as above with azide 1n (0.40 g, 1 mmol)
refluxed for 24 h, compound 3n (0.28 g, 80%) was also isolated as
white solid. Mp: 163–164 ꢀC, IR (KBr): 3278, 1657, 1633, 1530, 1350,
4.5.2. 2-(2-Azidophenyl)-N-(n-butyl)-2-hydroxyacetamide
(5b). Operation as above with n-butyl isocyanide (0.25 g, 3 mmol),
compound 5b (0.48 g, 65%) was also isolated as white solid. Mp:
48–49 ꢀC, IR (KBr): 3387, 3217, 2138, 2084, 1648, 1528, 1312,
1242 cmꢁ1 1H NMR (CDCl3, 400 MHz):
. d 8.96–7.27 (m, 8H, Ar-H),
6.33 (s, 1H, CONH), 5.86 (s, 1H, OCH), 3.33 (q, J¼6.8 Hz, 2H, NCH2),
1.51–1.45 (m, 2H, CH2), 1.32–1.27 (m, 2H, CH2), 0.88 (q, J¼7.2 Hz, 3H,
CH3). 13C NMR (CDCl3, 100 MHz):
d
167.4, 152.6, 148.3, 137.3, 133.5,
1074 cmꢁ1 1H NMR (CDCl3, 600 MHz):
. d 7.46–7.17 (m, 4H, Ar-H),
133.4, 129.9, 129.6, 128.0, 126.1, 125.6, 124.8, 122.7, 120.4, 75.8, 39.2,
6.41 (s, 1H, CONH), 5.29 (s, 1H, OCH), 4.17 (s, 1H, OH), 3.33–3.21 (m,
2H, NCH2), 1.49–1.43 (m, 2H, CH2), 1.31–1.26 (m, 2H, CH2), 0.89 (t,
31.3, 19.9, 13.6. MS m/z: 353 (Mþ, 3), 253 (100), 207 (33), 178 (11).

P. He et al. / Tetrahedron 65 (2009) 8563–8570
8569
J¼7.2 Hz, 3H, CH3). Anal. Calcd for C12H16N4O2: C, 58.05; H, 6.50; N,
isocyanate (0.14 g, 1 mmol) refluxed for 6 h, compound 8c (0.25 g,
22.57. Found: C, 58.17; H, 6.68; N, 22.51.
73%) was also isolated as white solid. Mp: 233–234 ꢀC, IR (KBr):
3408, 3377, 1666, 1643, 1509, 1482, 1214 cmꢁ1 1H NMR (CDCl3,
.
4.6. Synthesis of iminophosphoranes 6 via Staudinger
reaction
400 MHz):
d 9.52 (s, 1H, CONH), 7.90–6.93 (m, 9H, Ar-H and NH),
5.69 (s, 1H, OCH), 1.26 (s, 9H, 3CH3).13C NMR (DMSO-d6, 100 MHz):
d
167.7, 158.5, 156.1, 149.9, 140.6, 136.4, 129.0, 124.3, 122.6, 120.7,
4.6.1. N-(tert-Butyl)-2-hydroxy-2-(2-(triphenylphosphorany-lide-
ne)aminophenyl)acetamide (6a). To a stirred solution of azide 5a
(0.25 g, 1 mmol) in toluene (10 mL) was added dropwise triphe-
nylphosphine (0.26 g, 1 mmol) in toluene (5 mL) at room temper-
ature. After the reaction mixture was stirred for 4 h at ambient
temperature, the solvent was removed off under reduced pressure
and the residue was recrystallized from methylene dichloride/pe-
troleum ether to give 0.42 g (87%) of iminophosphorane 6a as white
115.2, 114.9, 75.7, 50.6, 28.3. MS m/z: 341 (Mþ, 22), 241 (100), 120
(22), 92 (17), 57 (80). Anal. Calcd for C19H20FN3O2: C, 66.85; H, 5.91;
N, 12.31. Found: C, 66.94; H, 5.75; N, 12.53.
4.7.4. N-(tert-Butyl)-2-(3-methylphenylamino)-4H-3,1-benzoxazine-
4-carboxamide (8d). Operation as above with 3-methylphenyl iso-
cyanate (0.13 g, 1 mmol) refluxed for 10 h, compound 8d (0.23 g,
67%) was also isolated as white solid. Mp: 188–190 ꢀC, IR (KBr):
solid. Mp: 206–208 ꢀC, IR (KBr): 3395, 3203, 1664, 1536, 1302 cmꢁ1
1H NMR (CDCl3, 400 MHz):
8.84 (s, 1H, CONH), 7.73–6.44 (m, 19H,
.
3384, 3301, 1666, 1641, 1593, 1483, 1222 cmꢁ1
400 MHz):
H), 5.69 (s, 1H, OCH), 2.28 (s, 3H, CH3), 1.27 (s, 9H, 3CH3). 13C NMR
(CDCl3, 100 MHz): 167.6, 149.9, 140.7, 139.6, 137.5, 128.9, 128.6,
.
1H NMR (CDCl3,
d
d 9.39 (s, 1H, NH), 7.88 (s, 1H, NH), 7.88–6.77 (m, 8H, Ar-
Ar-H), 5.76 (s, 1H, OH), 5.70 (d, J¼4.0 Hz, 1H, OCH), 1.09 (s, 9H,
3CH3). MS m/z: 482 (Mþ, 78), 381 (100), 353 (42), 277 (68),183 (91),
151 (53). Anal. Calcd for C30H31N2O2P: C, 74.67; H, 6.48; N, 5.81.
Found: C, 74.71; H, 6.42; N, 5.68.
d
128.3,124.3,122.5,120.7,119.5,116.2,115.3, 75.6, 50.5, 28.3, 21.3. MS
m/z: 337 (Mþ, 28), 237 (100), 91 (17), 57 (34). Anal. Calcd for
C20H23N3O2: C, 71.19; H, 6.87; N, 12.45. Found: C, 71.26; H, 6.73; N,
12.64.
4.6.2. N-(n-Butyl)-2-hydroxy-2-(2-(triphenylphosphorany-lidene)-
aminophenyl)acetamide (6b). Operation as above with azide 5b
(0.25 g, 1 mmol), iminophosphorane 6b (0.43 g, 90%) was also iso-
lated as white solid. Mp: 145–147 ꢀC, IR (KBr): 3389, 3212, 1658,
4.7.5. N-(n-Butyl)-2-(4-chlorophenylamino)-4H-3,1-benzoxazine-4-
carboxamide (8e). Operation as above with azide 5b (0.25 g, 1 mmol)
and 4-chlorophenyl isocyanate (0.15 g, 1 mmol) refluxed for 6 h,
compound 8e (0.25 g, 71%) was also isolated as white solid. Mp: 185–
186 ꢀC, IR (KBr): 3402, 3308, 1680, 1487, 1220 cmꢁ1. 1H NMR (CDCl3,
1545, 1304 cmꢁ1. 1H NMR (CDCl3, 400 MHz):
d 8.88 (s, 1H, CONH),
7.72–6.43 (m, 19H, Ar-H), 5.82 (s, 1H, OCH), 5.58 (s, 1H, OH), 3.22–
2.96 (m, 2H, NCH2), 1.13–1.04 (m, 4H, 2CH2), 0.65 (t, J¼7.2 Hz, 3H,
CH3). MS m/z: 482 (Mþ, 42), 381 (78), 353 (37), 277 (85), 183 (100),
209 (74), 151 (76). Anal. Calcd for C30H31N2O2P: C, 74.67; H, 6.48; N,
5.81. Found: C, 74.47; H, 6.34; N, 5.86.
400 MHz):
d 9.63 (s, 1H, NH), 8.28 (s, 1H, NH), 7.75–6.94 (m, 8H, Ar-
H), 5.76 (s, 1H, OCH), 3.37–3.03 (m, 2H, NCH2), 1.40–1.35 (m, 2H,
CH2), 1.27–1.19 (m, 2H, CH2), 0.83 (t, J¼7.2 Hz, 3H, CH3). 13C NMR
(CDCl3, 100 MHz):
d 168.0, 149.6, 140.2, 138.6, 129.1, 128.6, 128.4,
4.7. Synthesis of 2-amino-4H-3,1-benzoxazines 8
125.4, 124.6, 122.8, 120.5, 119.8, 75.7, 38.2, 31.0, 19.4, 13.6. MS m/z:
357 (Mþ, 32), 258 (100), 120 (25), 92 (17). Anal. Calcd for
C19H20ClN3O2: C, 63.77; H, 5.63; N, 11.74. Found: C, 63.95; H, 5.46; N,
11.78.
4.7.1. N-(tert-Butyl)-2-(isopropylamino)-4H-3,1-benzoxazine 4-car-
boxamide (8a). To a stirred solution of azide 5a (0.25 g, 1 mmol) in
toluene (10 mL) was added dropwise triphenylphosphine (0.26 g,
1 mmol) in toluene (5 mL) at room temperature. After the reaction
mixture was stirred for 4 h at room temperature, iso-propyl iso-
cyanate (0.09 g, 1 mmol) was added. The reaction mixture was
refluxed for 12 h and the solvent was evaporated under reduced
pressure. The residue was recrystallized from methanol to give
0.19 g (65%) of compound 8a as white solid. Mp: 147–148 ꢀC, IR
5. Crystallographic material
Crystallographic data for 3e have been deposited in the Cam-
bridge Crystallographic Data Center as supplementary publication
numbers CCDC 725169. Copies of the data may be obtained, free of
charge, on application to CCDC,12 Union Road, Cambridge, CB2 1EZ,
UK (fax: þ44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
(KBr): 3409, 3328, 1680, 1630, 1587, 1480, 1242 cmꢁ1
.
1H NMR
(CDCl3, 400 MHz): 7.30–6.98 (m, 4H, Ar-H), 5.98 (s, 1H, CONH),
d
5.40 (s, 1H, OCH), 4.43–4.33 (m, 1H, NCH), 4.07 (br, 1H, NH), 1.37 (s,
Acknowledgements
9H, 3CH3), 1.26–1.24 (m, 6H, 2CH3). 13C NMR (CDCl3, 100 MHz):
d
166.8, 151.7, 141.6, 129.5, 124.0, 122.8, 122.1, 119.6, 76.6, 51.4, 43.3,
We gratefully acknowledge financial support of this work by the
National Natural Science Foundation of China (No. 20772041) and
the Key Project of Chinese Ministry of Education (No. 107082).
28.5, 23.0. MS m/z: 289 (Mþ, 17), 189 (92), 147 (100). Anal. Calcd for
C16H23N3O2: C, 66.41; H, 8.01; N, 14.52. Found: C, 66.25; H, 8.17; N,
14.45.
Supplementary data
4.7.2. N-(tert-Butyl)-2-(4-chlorophenylamino)-4H-3,1-benzoxazine-
4-carboxamide (8b). Operation as above with 4-chlorophenyl iso-
cyanate (0.15 g, 1 mmol) refluxed for 6 h, compound 8b (0.21 g,
60%) was also isolated as white solid. Mp: 231–232 ꢀC, IR (KBr):
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.08.022.
3409, 3305, 1682, 1483, 1222 cmꢁ1 1H NMR (CDCl3, 400 MHz):
.
References and notes
d
9.62 (s, 1H, CONH), 7.92–6.93 (m, 9H, Ar-H and NH), 5.71 (s, 1H,
OCH), 1.26 (s, 9H, 3CH3). 13C NMR (DMSO-d6, 100 MHz):
d
167.6,
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´
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